Dravet Spectrum disorders resulting from SCN1A loss-of-function (LOF) mutations include febrile seizures, generalized epilepsy with febrile seizure plus (GEFS+), and Dravet Syndrome (DS), in order of severity. DS symptoms begin in infancy and lead to progressive developmental and behavioral impairments along with characteristic recurrent and varied seizures. In many patients, seizures are resistant to currently available antiepileptic drugs and uncontrolled seizures are associated with an increased incidence of SUDEP (sudden unexplained death in epilepsy). Thus, there is a significant and urgent need for the development of novel drug therapies. SCN1A-containing Nav1.1 channels functionally oppose the related SCN8A-containing Nav1.6 channels. Notably, introducing an SCN8A LOF mutation into a SCN1A LOF DS mouse model will ?rescue? the DS phenotype, ameliorating seizures and early death. Therefore, specifically reducing SCN8A-mediated excitation should rebalance the deficit of inhibitory input caused by SCN1A loss-of-function mutations and cause fewer adverse effects than sodium channel blockers which non-selectively antagonize multiple Na+ channels. SCN8A subunits are naturally alternatively spliced to produce a non-functional isoform. Thus, we developed novel compounds called splice modulating oligonucleotides (SMOs) that direct SCN8A pre-mRNA splicing to produce less functional isoforms of SCN8A protein. SMOs are a class of synthetic RNA based compounds that sterically block or weaken interactions between elements of the splice machinery and the pre- mRNA with exceptional potency, specificity, and negligible off-target effects at efficacious doses in CNS. SCN8A SMOs were designed in silico and refined for potency and specificity in vivo to identify two top SMO drug candidates. Preliminary testing of both candidate SMOs in a DS mouse model with an SCN1A LOF mutation largely eliminated seizures during a critical period and robustly increased survival. From these two candidates a lead SCN8A SMO will be selected to move forward into further pre-clinical testing. Non-GLP toxicology and pharmacodynamics testing will be performed in rats by the same intrathecal (i.t.) delivery method expected to be used in clinical trials. The single maximal tolerable dose (MTD) and no observed adverse effects (NOAEL) will be determined, followed by assessment of MTD and NOAEL at multiple doses (up to 4 weekly doses), and lastly studies to understand the duration of action at the MTD and NOAEL doses (Aim 1). Additional testing will be performed in DS mice to establish the MTD and the minimally effective SMO dose (MED) that reduces seizures, improves survival, and does not cause adverse motor effects or induce anxiety behaviors associated with SCN8A knockdown in mice (Aim 2). These studies are designed to continue pre-clinical testing in preparation for formal GLP-toxicology studies. The ultimate goal is to develop an SCN8A SMO as potential therapeutic for the treatment of Dravet Syndrome.